1-aroylpropyl-4-aryl-4-cyanopiperidines



3,069,426 Patented Dec. 18, 1962 SAW/E426 l-AROYLPROPYL-4-ARYL-4-=CYANOPIPERKDINE Paul A. J. .lanssen, Vosseiaar, near Turnhout, Belgium, assignor to Research Lahoratorium Dr. C. Janssen N.V., Beerse, Belgium, a company of Belgium No Drawing. Filed Apr. 27, 1960, er. No. 24,919 3 Claims. (Cl. 260--294.'7)

The present invention relates to a new group of cyanopiperidine derivatives and more particularly to l-aroylpropyl-4-aryl-cyanopiperidines of the general structural formula with an appropriately selected 4-aryl-4-cyanopiperidine.

The organic bases of this invention form pharmaceutically acceptable salts with a variety of inorganic and strong organic acids, including sulfuric, phosphoric, hydrochloric, hydrobromic, hydriodic, sulfamic, citric,

lactic, maleic, malic, succinic, tartaric, cinnamic, acetic,

benzoic, gluconic, ascorbic, and related acids. They also form quaternary ammonium alts with a variety of organic esters of sulfuric, hydrohalic and aromatic sulfonic acids. Among such esters are methyl chloride and bromide, ethyl chloride, propyl chloride, butyl chloride, isobutyl chloride, benzyl chloride and bromide, phenethyl bromide, naphthylmethyl chloride, dimethylsulfate, diethylsulfate, methyl benzenesulfanate, ethyl toluenesulfonate, ethylene chlorohydrin, propylene chlorohydrin, allyl bromide, methallyl bromide and crotyl bromide.

The preparation of these compounds will appear more fully from a consideration of the following examples which are given for the purpose of illustration only and are not to be construed as limiting the invention in spirit or in scope. In these examples quantities are indicated as parts by weight, temperatures in degrees centigrade C.), and pressure in millimeters of mercury (mm.).

Example 1 To a mixture of 119 parts of N,N-( B,,6-dihydroxy)diethyl amine and 54 parts of 2 N sodium carbonate are added 190.5 parts of 4-toluenesulfony1 chloride. This mixture is heated to about 95 C. for about one hour and then cooled to 0 C. and filtered. The filtrate is extracted with ether. After evaporation of the ether, the residue is crystallized from a mixture of 2-propanol and petroleum ether by chilling at 20 C., and then recrystallized from a 1:3 by volume mixture of ethanol and acetone to yield N-( i-toluenesulfonyl)-N,N-(;3,fl-dihydroxy)diethyl amine. A mixture of this compound and 690 parts of thionyl chloride is heated gently at 125 C. for about an hour and then cooled. The excess thionyl chloride is evaporated and the residue is purified by crystallization from dry toluene to yield N-(4-toluenesulfonyl) -N,N- [3,{i-dichloro -diethyl amine.

To a solution of 592.5 parts of this compound and 270 parts of 4-fluorophenylacetonitrile in 2000 parts of dry toluene are added portionwise 345 parts of a 50% suspension by Weight of sodamide in xylene while the temperature is maintained at about 45-50 C. After the initial reaction has subsided, the mixture is heated slowly to boiling and then refluxed for 2 hours. After cooling, water is added to decompose the mixture. The precipitate is collected, washed with 2-propanol, and dried to yield 1 (4 toluenesulfonyl) 4-cyano 4 (fluorophenyl)piperidine melting at about 1865-188 C.

By substituting the appropriate starting materials in the above procedure, the following compounds are obtained:

l-(4-toluenesulfonyl)-4-cyano-4-phenylpiperidine.

1 (4 toluenesulfonyl) 4 cyano 4 (3 tolyl)- piperidine.

1 (4 toluenesulfonyl) 4 cyano 4 (4 tolyl)- piperidine.

1 (4 toluenesulfonyl) 4 cyano 4 -(3 fluorophenyDpiperidihe.

1 (4 toluenesulfonyl) 4 cyano 4 (4 iodophenyl)piperidine.

l (4 toluenesulfonyl) 4 cyano 4 (4 chlorophenyl)piperidine.

Example 2 A mixture of 52.5 parts of l-(4-toluenesulfonyl)-4- cyano-4-(4-chlorophenyl)piperidine, 26.4 parts of phenol, 322 parts of a 30% solution of hydrogen bromide in acetic acid is heated for 24 hours at about 40 C., cooled, and filtered. The precipitate is saved. The filtrate is poured into dry ether and the solid which precipitates is collected and combined with the precipitate saved from above. This combination is dissolved in water. The solution is then boiled with activated charcoal, rendered alkaline, and extracted with ether. The extract is then evaporated to yield 4-cyano-4-(4-chlorophenyl)piperidine melting at about 77-78.5 C.

By substituting equivalent quantities of the starting materials in the above procedure, the following compounds are obtained:

. 4-cyano-4-pheny1piperidine.

4-cyano-4-(3-tolyl)piperidine. 4-cyano-4-(4-to1yl)piperidine. 4-cyano-4-(3-fluorophenyl)pipe1idine. 4-cyano-4- (4-iodophenyl) piperidine. 4-cyano-4-(4-chlorophenyl)piperidine.

Example 3 A mixture of 5.4 parts of -chlorobutyrophenone, 5.5 parts of 4-cyano-4-phenylpiperidine, 7.8 parts of sodium carbonate, and 0.1 part of potassium iodide in 120 parts of 4-methyl-2-pentanone is refluxed for hours, cooled, and partitioned between water and ether. The ether layer is separated, diluted with additional ether and dried. Hydrogen chloride gas is passed through the solution. The solid precipitate is collected on a filter and then recrystallized from acetone by chilling at 20 C. to yield 1 ('y benzoylpropyl) 4 cyano 4 phenyl piperidine hydrochloride melting at about 206207.6 C.

By substituting 4-cyano-(3-fluorophenyl)-piperidine in the procedure of the above paragraph, l-(y-benzoylpropyl)-4-cyano-4-(3-fluorophenyl)piperidine hydrochlo- Example 7 W16 of structural formula Arnixture of 4 parts of -chloro-4-fiuorobutyrophenone, @N 9.1 parts of 4-cyano-4-(4-chlorophenyl)-piperidine, 0.1 oO-CH -cH -cH -N part of potassium iodide, and 120 parts of toluene is heated in a sealed tube for 90 hours at about 120 C. F and then cooled. The filtrate is washed with water, dried, decolorized with activated charcoal, and evaporated. The Obtamedresidue is dissolved in a mixture of diisopropyl ether and Example 4 10 ether. TIgydrogen chloride gas is passed through the solution. e solid which reci itates is collected on a filter To a suspensmn of 341 parts of alummum chlonde and then dissolved in iiot ater. Upon acidifying the in 1740 parts of carbon disulfide are added 96 parts of hot a queous solution to a pH of about 1 and coohng, a f i f g Y i g i g igl i solid precipitates. The solid is collected on a filter and fi fi g a a 25 d th 3339 7' then crystallized from 2-propano1 to yield 1-[ -(4-fiuoroc Om n W e e are a e 6 a IS 5 benzoyl)propyl] 4-cyano-4-(4-chlorophenyl)piperidine completed, the COOllIlg bath is removed and the stirring hydrochloride melting at about 242 5 243 so C is continued for about 2 hours. The reaction mixture is By substituting chlorobenzene 1n the first paragraph of g sg fi f g zf gg tigg i fi ig Example 4, 'y,4-dichlorobutyrophenone is obtained. This s 5 W1 d t t o m 2 a compound is then substituted for 'y-chloro-4-fluorobutyroan tare e a e f F ae er re 20 phenone and 4-cyano-4-(4-iodophenyl)piperidine for 4- pressure, and the res1du e 1s distilled to yield 'y chloro-4- cyano 4 (4 chlomphenyl)piperidine in the Procedure of fi gigg gg boflmg at about 136442 at 6 the above paragraph and 1-[' -(4-ch1orobenzoyl)propyl]- The free base of 4-cyano-4-phenylpiperidine hydrochlofggg P1P emdme hydrochlonde 1s ride is liberated by dissolving 14.2 parts of the salt in Example 8 water, rendering the solution alkaline, extracting the solution with ether, and drying and evaporating the ether extract. The residue, 6.4 parts of 'y-chloro-4-fiuorobutyrophenone, 0.1 part of potassium iodide, and 120 parts of toluene is heated in a sealed tube for 96 hours at 110l20 C., cooled, and filtered. The filtrate is partitioned between water and ether, and the layers are separated. The organic layer is first dried and then hydrogen chloride gas is introduced into the solution. The precipitate is collected, crystallized from a 2:1 mixture of acetone and 2-propanol, and then recrystallized from a 3:1 mixture of acetone and 2-propanol by allowing the solution to stand for 2 days at room temperature to yield 1-['y-(4-fluorobenzoyl)propyl]-4-cyano-4-phenylpiperidine hydrochloride melting at about 224.5-230.4 C.

A Grignard reagent of 3-fluorophenylmagnesium bromide is prepared by reacting 6.7 parts of magnesium with 94.5 parts of 3-bromofluorobenzene in 80 parts of ether. Then 21 parts of 'y-chlorobutyronitrile in 64 parts of ether are added and the mixture is refluxed under nitrogen for two hours with stirring. The mixture is then allowed to stand at room temperature for 15 hours and the excess Grignard reagent is decomposed by the addition of 56 parts of concentrated hydrochloric acid and parts of Water. The organic layer is separated, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue is distilled to yield 'y-chloro- 3-fluorobutyrophenone boiling at about l05-125 C. at 2 mm. pressure.

I Substitution of 'y-chloro-3-fluorobutyrophenone in the Example 5 procedure of Example 6 yields 1-['y-(3-fluorobenzoyl)- n propyl]-4-cyano-4-(4-tolyl)piperidine. fi if gf ggg gjf g gaggi gf gzg i By subst1tut1ng 3-b1'om0t01ue ne 1n the first paragraph potassium iodide, and 120 parts of toluene is heated in examplet i t f 1S a sealed tube at about 120 C., cooled, and then filtered. tamed An eqmmolar Q of this Compound for The filtrate is washed with water, boiled with activated 'fl m the Procedure of charcoal, and then evaporated. The residue is dissolved ample 6 f' v4 y ybpropyl]-4-cyanoin diisopropyl ether. The solution is chilled at 20 4'(4'tlyl)p1pendme of the structural formula C. to yield 1-['y-(4-fluorobenzoyl)propyl]-4-cyano-4-(3- 50 3 0N tolyl)piperidine melting at about 79.6-72.8 C. as a pre- 6 CWCHT cipitate. The hydrochloride of this compound melts at By substituting bromobenzene in the first paragraph y F of Example 4, 'y-chloro-4-bromobutyrophenone is. ob- H tained. An equimolar substitution of this compound for What is claimed is:

Y 'y-chloro-4-fiu0robutyrophenone in the above paragraph 1. A compound of the formula and otherwise following the outlined procedure, yields 1- (m ['y (4 bromobenzoyDpropyl] 4 cyano-4-(3-tolyl)- T W A z piperidine. The compound has the structural formula 60 0N Br co-cn -ca -cn -u w- CH Example 6 wherein Ar and Ar are members of the class consisting of phenyl, tolyl, and halophenyl. A mixture of 4 parts of 'y-chloro-4-fluorobutyrophenone, 8.2 parts of 4-cyano-4-(4-tolyl)piperidine, 0.1 part1 of 4 p 1-1eI y-l'pi[1;ridi(:e fl I'ObGHZOYDpropyl] 4 cyan). potassium iodide, and 120 parts of toluene is heate 1n a sealed tube for 90 hours at 120 c. and then filtered. 3- 3 T gi Y 4 crane The filtrate is washed with water, dried over sodium suly pm 1 fate, boiled with activated charcoal, and then evaporated. References Cited in the file of this patent The residue is crystallized from diisopropyl ether by chilling at 20 c. to yield l-[y-(4-fluorobenzoyl) UNITED STATES PATENTS propyl]-4-cyano-4-(4-t0lyl)-piperidine melting at about 2,248,018 Eisleb July 1, 1941 5.9 5 c, 2,807,585 Gardner Sept. 24, 1957 

1. A COMPOUND OF THE FORMULA 